The sensation of pain functions as a natural warning sign that an injury has occurred or is about to occur and is meant to trigger a protective response. In many cases, however, the sensation of pain remains as persistent chronic inflammatory or cancer pain and becomes debilitating both physically and psychologically. Pain is the primary symptom that motivates people to seek medical treatment, accounting for over 35 million new office visits to physicians and over 70 million (80%) of all office visits to physicians each year in the United States. Pain medications are the second most frequently prescribed medications (after cardiac-renal therapeutics) during visits to physicians' offices and emergency rooms. Almost one in five adult Americans (a total of about 50 million) experiences chronic pain; 17% of patients in the United States seen by primary care physicians suffer from persistent pain; and 4.9 million people seek treatment for chronic pain each year.
As Julius and Basbaum note, pain is a complex experience that, besides the transduction of noxious environmental stimuli, also involves cognitive and emotional processing by the central nervous system (Julius D & Basbaum A I, 2001 Nature 413, 203-210).
TGF-β and other members of its superfamily including activin and bone morphogenetic proteins (BMP) are recognized as playing critical roles in the development, survival and repair of neurons in the peripheral and central nervous systems (CNS). Böttner M. et al., 2000 J. Neurochem., 75, 2227-40. However, little is known about the peripheral effects of TGF-β on nociception although its expression is increased in chronic inflammation, where it plays a key role in wound healing and promoting fibrosis. Pohlers D. et al., 2009 Biochim Biophys Acta., 1792, 746-56. Ongoing tissue injury and inflammation initiate a cascade of events resulting in peripheral sensitization, i.e., enhancement of the responsiveness of primary afferent neurons (nociceptors), whose bodies are housed in dorsal root ganglia (DRG) and whose central ends synapse with second order neurons in the spinal cord. Sensitized nociceptors display increased spontaneous activity as well as increased responsiveness to both noxious and non-noxious stimulation.
Many of the current therapies for pain unspecifically fight inflammatory agents and often have limitations in their efficacy either due to development of tolerance following a certain time period of treatment or due to undesired or even unacceptable side effects such as nausea, sedation and so forth. Consequently, there is an unmet medical need for compositions and methods for treating pain more selectively. The present invention addresses this need.